Second-line therapies for advanced HR+/HER2- breast cancer

HR-positive/HER2-negative breast cancer is the most common subtype of breast cancer. Breast cancers in this subtype have hormone receptors that can bind to estrogen and/or progesterone, hormones that cancer cells can use to fuel their growth. These cancers also lack large amounts of human epidermal growth factor receptor 2 (HER2), a substance that other cancers use to drive growth and spread.

Hormone receptors and HER2 are both examples of biomarkers. Knowing a cancer’s biomarkers helps healthcare teams predict what treatments a cancer is most likely to respond to.

Initial treatment for advanced or metastatic HR-positive/HER2-negative breast cancers typically includes endocrine therapy, also known as hormone therapy. These are cancer treatments that reduce the amount of estrogen in the body. This can slow or stop the growth of HR-positive breast cancers.

However, up to half of HR-positive/HER2-negative breast cancers do not respond or stop responding to this treatment. This is especially common in advanced and metastatic breast cancers.

If HR-positive/HER2-negative breast cancer is no longer responding to endocrine therapy, your healthcare team will discuss other treatment options.

Second-line treatment with targeted therapies

Due to mutations in cancer cell DNA, proteins that normally regulate the growth, division, and survival of cells can behave abnormally. Instead of regulating the lifecycle of healthy cells, these abnormal substances promote the uncontrolled growth and spread of cancer cells.

There are drugs that can target some of the altered proteins that occur as a result of these mutations. This category of cancer treatment is called targeted therapy or molecularly targeted therapy.

With advanced HR-positive/HER2-negative breast cancer, targeted therapies are the main recommendation for second-line treatment.

To determine if targeted therapy is an option—and if it is, what targeted therapy to use—a healthcare team may order additional diagnostic tests or revisit existing test results. This may include molecular profiling, a type of biomarker testing that uses blood samples or tumor tissue biopsies to look for acquired genetic mutations that can be driving cancer growth.

ESRI mutations

These mutations create estrogen receptors that are always active, even when estrogen isn’t present. Active estrogen receptors cause cells to grow and divide. Drugs called SERDs (selective estrogen receptor degraders) attach to and damage the mutant receptors, which are then removed by the cell.

Mutations to the PIK3CA, AKT1, and PTEN genes

These genes contain instructions for making proteins that play a critical role in controlling a cell’s growth, survival, and expiration. Mutations change how these proteins work, which helps cancerous cells grow and divide faster than normal cells, and also survive longer than normal cells.

There are targeted therapies that act on these abnormal proteins, stopping or slowing cancer cell growth. These drugs are used in combination with hormone therapy, and some enhance how cancer responds to hormone therapy.

BRCA 1/2 mutations

BRCA genes make proteins that repair DNA errors. Mutations to these genes create nonfunctioning proteins, causing cells to accumulate more and more errors in DNA, which can lead to or contribute to cancer. Cancerous cells with certain BRCA mutations are vulnerable to targeted drugs called PARP inhibitors, which block an enzyme that these cancerous cells need to survive.

What if these mutations are not present?

Other types of therapies may be prescribed if there are no actionable mutations.

mTOR inhibitors

A type of targeted therapy called an mTOR inhibitor can be used even if there are no actionable mutations. This drug blocks the mTOR protein and interferes with cell survival, growth, and the development of new blood vessels that feed tumors. An mTOR inhibitor will be taken in combination with a hormone therapy.

Antibody drug conjugates

A healthcare team may also recommend a type of drug called an antibody drug conjugate. These drugs are a combination of a monoclonal antibody and chemotherapy drug. A monoclonal antibody is a protein that attaches to specific types of cells—in this case cancer cells. It helps to deliver the chemotherapy part of the drug to cancer cells with greater precision.

Additional treatment options

Other treatment options can include additional endocrine therapy drugs and/or CDK 4/6 inhibitors. Standard chemotherapy may also be an option in some cases, but this treatment is usually used when other treatments have been tried.

Your healthcare team is your best source of information

It’s important to remember that different drugs work for different people. Ask your healthcare team to explain what therapies are being recommended to you and why. Discuss potential side effects, including any risk of serious side effects.

Treatment options for second-line therapies have improved over the past decade and continue to improve. New therapies, emerging therapies, updates to treatment guidelines, and clinical trials are topics worth discussing with your healthcare team, who will be your best source of information.